Claims:1) A process for preparation of Iguratimod of formula-I comprising;

a) reacting 4-chloro-3-nitroanisole with phenol in presence of a base and a catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II; and

b) further converting the compound of 3-nitro-4-phenoxyanisole of formula-II into Iguratimod of formula-I.

2) The process as claimed in claim 1, wherein the base is selected from group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
3) The process as claimed in claim 1, wherein the catalyst is selected from group consisting of cuprous chloride (CuCl), cupric chloride (CuCl2), cuprous bromide (CuBr), cupric bromide (CuBr2), cuprous iodide (Cul) and cupric acetate (Cu(OAc)2).
4) The process as claimed in claim 1, wherein the hydrocarbon solvent is selected from group consisting of benzene, toluene, p-xylene, m-xylene, chlorobenzene, 1,2,3-trimethylbenzene and 1,3,5-trimethylbenzene.
5) The process as claimed in claim 1, wherein the hydrocarbon solvent is toluene.
6) A process for preparation of 3-nitro-4-phenoxyanisole of formula-II comprising reacting 4-chloro-3-nitroanisole with phenol in presence of a base, catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II.
7) The process as claimed in claim 6, wherein the 3-nitro-4-phenoxyanisole of formula-II is further converted to Iguratimod.
8) The process as claimed in claim 6, wherein the hydrocarbon solvent is selected from group consisting of benzene, toluene, p-xylene, m-xylene, chlorobenzene, 1,2,3-trimethylbenzene, 1,3,5-trimethylbenzene.
9) The process as claimed in claim 6, wherein the hydrocarbon solvent is toluene.

, Description:Field of the invention:

The present invention relates to a new process for preparation of Iguratimod of formula-I. More particularly, the invention relates to preparation of intermediate of formula-II useful in the preparation of Iguratimod.

Background of Invention:

Iguratimod, chemically known as N-[(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl] methanesulfoanamide, is an anti inflammatory agent used for the treatment of rheumatoid arthritis. Preparation of Iguratimod was first reported in the US4954518. As per the teachings of US4954518 and Chem.Pharm.Bull., 2000, 48, 131-139, Iguratimod was prepared starting from 3-nitro-4-phenoxy anisole or 3-nitro-4-phenoxy phenol. The intermediate, 3-nitro-4-phenoxy anisole was generally prepared from of 4-chloro-3-nitroanisole with phenol.

US4411910 patent reported preparation of 3-nitro-4-phenoxy anisole by condensing 4-chloro-3-nitroanisole with phenol in presence of CuCl catalyst and potassium carbonate in pyridine. In this process, pyridine is used as solvent and this process found to be giving low yield of 3-nitro-4-phenoxy anisole. Also this process involves additional purification step causing the increase in production cost and time cycle.

Other publications, Chemical and Pharmaceutical Bulletin. 48(1) 131-139 (2000) and IN1507/MUM2014 belongs to the present applicant reported preparation of 3-nitro-4-phenoxy anisole by reacting 4-chloro-3-nitroanisole with phenol in presence of potassium tertiary butoxide and dimethylformamide solvent. However, this process involves use of combination of dimethylformamide- potassium tertiary butoxide which is hazardous and raises safety issues, therefore, this process is not suitable for large scale operations. Moreover, the dimethylformamide is not completely recovered and recycled increasing the cost of production.

Therefore, there is very much necessity to develop an improved industrially feasible and economically viable process to prepare the intermediate, 3-nitro-4-phenoxy anisole, to overcome the problems of the prior art. The present invention addresses the need by providing an alternative industrially feasible economical process to prepare the intermediate, 3-nitro-4-phenoxyanisole and further converting the intermediate into Iguratimod.

Summary of Invention:

Accordingly the present invention provides a cost-effective and commercially viable process for preparation of Iguratimod and also provides a process for preparation of its intermediate, 3- nitro -4- phenoxyanisole.

According to one aspect, the present invention provides a process for preparation of Iguratimod of formula-I comprising;

a) reacting 4-chloro-3-nitroanisole with phenol in presence of a base and a catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II; and

b) further converting the compound of 3-nitro-4-phenoxyanisole of formula-II into Iguratimod of formula-I.

In a preferred embodiment, 4-chloro-3-nitroanisole is reacted with phenol in presence of potassium carbonate, cuprous chloride catalyst in toluene solvent to obtain 3-nitro-4-phenoxyanisole of formula-II.

According to another aspect, the present invention provides a process for preparation of 3-nitro-4-phenoxyanisole of formula-II comprising reacting 4-chloro-3-nitroanisole with phenol in presence of a base, catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II;

Detailed description of the invention:

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. The term "consists essentially of” means excluding other materials that contribute to function.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
It has bow been found that an improved economical process to prepare 3-nitro-4-phenoxyanisole of formula-II by reacting 4-chloro-3-nitroanisole with phenol in presence of a base and a catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II and further conversion of the 3-nitro-4-phenoxyanisole of formula-II into Iguratimod. The various aspects of the invention are described in detail with the preferred embodiments/conditions hereafter.

Accordingly, in one aspect, the present invention provides a process for preparation of 3-nitro-4-phenoxyanisole of formula-II comprising reacting 4-chloro-3-nitroanisole with phenol in presence of a base, catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II.

The bases employed for this reaction are preferably selected from metal alkoxide, carbonates or bicarbonates. Exemplary bases include, but not limited to sodium/potassium hydroxide, sodium/potassium carbonates or bicarbonate or the like. However preferred base is potassium carbonate.

The catalyst used for this coupling reaction may be selected from Cu(I) or Cu(II) salts such as cuprous chloride (CuCl), cupric chloride (CuCl2), cuprous bromide (CuBr), cupric bromide (CuBr2), cuprous iodide (Cul) or cupric acetate (Cu(OAc)2). However preferred catalyst is cuprous chloride (CuCl).

The hydrocarbon solvent may be aliphatic or aromatic in nature. Aliphatic hydrocarbons may be selected from hexane, pentane, dodecane or cyclohexane etc., and, aromatic hydrocarbons may be selected from benzene, toluene, p-xylene, m-xylene, chlorobenzene, 1,2,3-trimethylbenzene, 1,3,5-trimethylbenzene etc., However, preferred solvent is toluene.

The reaction may be carried out at above ambient temperature to reflux temperature of the solvent used. Usually the reaction completes in 22-26 hours.
After completion of reaction, the salt is separated by filtration. The filtrate containing the product is washed with dilute sodium hydroxide. Separated layers and organic layer is concentrated to isolate the product.

According to another aspect, the present invention provides a process for preparation of Iguratimod of formula-I comprising; reacting 4-chloro-3-nitroanisole with phenol in presence of a base, catalyst in hydrocarbon solvent to obtain 3-nitro-4-phenoxyanisole of formula-II; and further converting the 3-nitro-4-phenoxyanisole of formula-II into Iguratimod of formula-I.

In a preferred embodiment, wherein the hydrocarbon solvent is toluene, base is potassium carbonate and catalyst is cuprous chloride, the present invention provides a process for preparation of Iguratimod as per the Scheme-I mentioned below.
Scheme-1:

The 3-nitro-4-phenoxyanisole of formula-II obtained as per the present invention is converted into Iguratimod by subjecting the 3-nitro-4-phenoxyanisole for reduction using H2 in presence of Raney Nickel catalyst and ethyl acetate solvent to obtain amino compound of Formula-III. The amino compound of Formula-III is reacted with methane sulfonyl chloride in presence of pyridine in methylenedichloride solvent to obtain corresponding sulfonyl derivative of the amino compound of Formula –IV. The sulfonyl compound of Formula –IV is further reacted with aminoacetonitrile hydrochloride in presence of anhydrous aluminium chloride (AlCl3) in nitrobenzene solvent followed by reacting with dry HCl to obtain compound of Formula-V. The compound of Formula –V is further reacted with sodium formate in presence of pivaloyl chloride in acetone solvent to obtain the compound of Formula-VI. The compound of Formula-VI is reacted with aluminium chloride in presence of sodium iodide in acetonitrile solvent to get the phenolic compound of Formula-VII. Finally the phenolic compound of Formula-VII is subjected to cyclisation by reacting with dimethyl formamide dimethylacetal in dimethylformamide solvent to form Iguratimod. The product may be purified by known methods such as crystallization or base-acid treatment.

The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Stage-I: 4-Chloro-3-nitro anisole (CNA)
In a clean 3.0 Lit 4-neck R.B. flask, charged 100 g (0.595 moles) of 4-Methoxy-2-nitroaniline, 300 ml water and 500 ml con.HCl. A solution of sodium nitrite (123.21 g (1.786 moles) dissolved in 170 ml water) was added drop-wise into the reaction mass at -5 to 50C. To the above reaction mass, 300 ml toluene was charged. A solution of cuprous chloride (176.78 g 1.786 moles in 700 ml of con. HCl) was added drop-wise into the reaction mass at -5 to 50C. After complete addition, reaction mass was heated to 55-600C and maintained upto completion of reaction. After completion of reaction, reaction mass was cooled to room temperature, filtered through hyflo bed and washed with toluene. The organic layer was separated and aqueous layer was extracted with toluene and combined with the main organic layer. The combined organic layer was washed with water. The organic phase was concentrated under vacuum and obtained 4-Chloro-3-nitroanisole.
Yield: 100 g (90%)

Stage-II: 3-Nitro-4-phenoxy anisole (NPA)
In a clean and dry 2 Lit 4-neck R.B.flask, charged 100 g (0.769 moles) of potassium carbonate, 500 ml of toluene, and then 55.20 g of phenol (0.586 moles) was charged in the above reaction mass at 55-600C and stirred for 30 min. To the above reaction mass, 100 g (0.533 moles) of 4-chloro-3-nitroanisole and 10 g of CuCl (10%) were added. The above reaction mass was heated to 105-1100C upto completion of reaction. After completion of reaction, the reaction mass was cooled to RT, filtered through hyflo bed and washed the hyflo bed with toluene. The organic layer was washed first with 5% NaOH, followed by 2% HCl solution and finally with water. The organic phase was concentrated under vacuum to obtain 3-Nitro-4-phenoxy anisole.
Yield: 110 g (84%)

Stage-III: 3-Amino-4-phenoxy anisole (APA)
Into a 2.0 lit autoclave, charged 800 ml of ethyl acetate followed by 100 g (0.408 moles) of 3-Nitro-4-phenoxy anisole and stirred for 10-15 minutes. Charged 5 g (10%) of Raney Nickel into the solution in the autoclave. Flushed the reaction mass twice with nitrogen, followed by flushing with hydrogen and then applied hydrogen pressure at 10-12 kg/cm2 and heated the reaction mass to 40-45°C. Maintained the reaction mass at 40-45°C for 12-15 hrs till completion of reaction. After completion of reaction, the reaction mass was filtered through hyflo bed (20 g) to filter out Raney Nickel catalyst and washed the hyflo bed with ethyl acetate. Ethyl acetate was distilled out under vacuum. Then water was added into the concentrated reaction mass and heated to 50-550C. The Solid precipitated out was filtered, washed with water and dried under vacuum to get 3-Amino-4-phenoxy anisole (APA).
Yield: 82 g (93%)

Stage-IV: 3-Methyl sulfonyl amino-4-phenoxy anisole (SPA)
In a clean and dry 2.0 Lit 4-neck R.B.flask, 100 g (0.465 moles) 3-Amino-4-phenoxy anisole, 110.23 g (1.395 moles) pyridine and 450 ml methylene dichloride (MDC) were charged. To the above reaction mass, a solution of methane sulfonyl chloride (58.61 g, 0.512 moles dissolved in 150 ml MDC) was added drop-wise at 0-50C. Maintained the reaction mass at 25-300C up to completion of reaction. After completion of reaction, water was added and adjusted pH of the reaction mass to 2.5 to 3.0 with 4 N HCl solution. The organic layer was separated and washed with water. MDC was distilled out at 40-450C. 200 ml ethanol was added to the residue and heated to 65-700C. Reaction mass was cooled to 0-50C. Solid separated was filtered, washed with chilled ethanol and dried under vacuum.
Yield: 120 g (88%)

Stage-V: Alpha-amino-2-methoxy-4-methanesulfonylamino-5-Phenoxy acetophenone hydrochloride (SPA.HCl):
In a clean and dry 2.0 Lit 4-neck R.B. flask, 90.71 g (0.680 moles) aluminium chloride, 37.7 g (0.408 moles) amino acetonitrile hydrochloride and 300 ml nitrobenzene was charged under nitrogen and stirred the reaction mass for 1 hr at 40-450C. 100 g (0.3401 moles) 3-methyl sulfonyl amino-4-phenoxy anisole was charged in the above reaction mass at 10-150C. HCl gas was purged in the above reaction mass for 6-8 hrs. After complete purging of HCl gas, reaction mass was maintained at 10-150C upto completion of reaction. After completion of reaction, 4N HCl was added at 0-50C and stirred the reaction mass for 4-5 hrs at 0-50C. The solid separated was filtered and washed with water. The crude separated was purified with ethyl acetate by slurrification at 65-700C and further cooling to 0-50C. Solid separated was filtered, washed with chilled ethyl acetate and dried under vacuum.
Yield: 114 g (86%)

Stage-VI: Alpha-formamido-2-methoxy-4-methylsulfonylamino-5-phenoxy acetophenone (SPAF):
In a clean and dry 2.0 Lit 4-neck R.B. flask, charged 75.85 g (0.622 moles) trimethyl acetyl chloride, 81.04 g (1.192 moles) sodium formate and 300 ml acetone was charged under nitrogen. The reaction mass was stirred for 4-5 hrs at 0-50C. 100 g (0.259 moles) Alpha-amino-2-methoxy-4-methanesulfonylamino-5-Phenoxy acetophenone hydrochloride was charged into the above reaction mass. Reaction was maintained at 30-350C upto completion of reaction. After completion of reaction, water was added at 0-50C and stirred the reaction mass for 5-6 hrs at 0-50C. The solid separated was filtered and washed first with chilled water and then with chilled i-propanol. The solid was dried under vacuum.
Yield: 70 g (72%)

Stage-VII: Alpha-formamido-2-hydroxy-4-methanesulfonyl-amino-5-Phenoxy acetophenone (DSPAF):
In a clean and dry 2.0 Lit 4 neck R.B.flask, charged 300 ml of acetonitrile, 81.13 g (0.608 moles) of aluminium chloride, 51.69 g (0.344 moles) of sodium iodide and 100 g (0.264 moles) of alpha-formamido- 2-methoxy-4-methylsulfonylamino-5-phenoxy acetophenone under nitrogen at 10-150C. Maintained the reaction mass at 10-150C upto completion of reaction. After completion of reaction, 1% sodium sulfite solution was added at 0-50C and stirred the reaction mass, solids separated was filtered and washed with chilled water and then with chilled ethanol. The solid was dried under vacuum at 60-650C.
Yield: 80 g (83%)

Stage-VIII: 3-(formamido)-7-(methylsulfonylamine)-6-(phenoxy)-4H-1- (benzopyran)-4-one (IGRD):
In a clean and dry 2.0 Lit 4-neck R.B.Flask, 100 g (0.274 moles) of Alpha-formamido-2-hydroxy-4-methanesulfonyl-amino-5-phenoxy acetophenone and 200 ml dimethyl formamide were charged. 98.10 gm (0.823 moles) of dimethyl formamide. dimethyl acetal solution was added drop-wise into the above reaction mass at 5-100C. Maintained the reaction mass at 15-200C upto completion of reaction. After completion of reaction, charged MDC and water into the reaction mass. pH of the reaction mass was adjusted to 2-3 with 10% HCl solution and maintained the reaction mass at 0-50C for 2-3 hrs. The solid separated was filtered and washed with water and then with mixture of MDC: water: Ethanol (600 mL: 200 mL: 200 mL: 200 mL). The solid was dried under vacuum at 100-1050C.
Yield: 84 g (81%)

Stage IX: Purification of 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy)- 4H-1- (benzopyran)-4-one (IGRD pure):
In a clean and dry 3.0 Lit 4-neck R.B.flask, 100 g (0.267 moles) 3-(formamide)-7-(methylsulfonylamine)-6-(phenoxy)-4H-1-(benzopyran)-4-one, 1000 ml water and 1000 ml acetonitrile were charged. pH of the above reaction mass was adjusted to 10-10.5 with 10% sodium carbonate solution. The above clear reaction mass was filtered through micron filter. Again pH of the above clear reaction mass was readjusted to 1.5-2.0 with 10% HCl solution. Solid separated was filtered, washed with water and dried under vacuum at 100-1050C to obtain Iguratimod as solid powder.
Yield: 95 g (95%)